Hyaluronic acid (hereinafter, “HA”) is a glycosaminoglycan with repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine that exists as a high molecular mass polymer (106 to 107 Da) in its native form (Laurent et al. FASEB J. 6:2397, 1992). HA is a major non-structural component of connective tissue and is important for maintaining extracellular matrix architecture and for promoting cell motility, adhesion and proliferation (Entwistle, J. Cell Biochem. 61:569, 1996).
The effects of both low molecular mass HA (≦5×105 Da) and high molecular mass HA (>5×105 Da) on normal cells has been studied extensively (McKee et al. J. Biol. Chem. 272:8013, 1997; Hodge-Dufour et al. J. Immunol. 159:2492, 1997; Rooney et al. Int J Cancer 60:632, 1995). However, little is known about the effects of HA on malignant cells. In vitro, HA (>0.320 mg/ml) inhibited proliferation of B16F10 murine melanoma cells by 50 to 90%. In vivo, HA (1 mg/ml), administrated over 7 days by an Alzet osmotic pump into the immediate vicinity of a B16F10 murine melanoma tumor, reduced tumor volume >85%. In vivo, HA (>750 mg/kg) administered with various other therapeutic agents over various periods of time, reduced or eliminated rectal, gastric, breast, prostate and endometrial cancers (PCT/CA/00283). In vivo, hyaluronan (HA) (7.5 mg/kg), administered with 2.5 mg/kg of the lipophilic, tubulin-stabilizin, chemotherapeutic drug paclitaxel (TAXOL®), decreased tumor mass of colon 26-cells seeded into BALB/c mice. It was proposed that the water-insoluble paclitaxel binds to hydrophobic patches on HA and that the binds to HA receptors on the surface of malignant cells and, thereby, delivers the paclitaxel directly to the malignant cells (PCT/CA98/00660) That is, HA functions as a delivery agent for the paclitaxel and the efficiency of this delivery depends on the expression of HA cell surface receptors such as CD44. However, as colon-26 cancer cells express high levels of HA receptors, HA alone significantly inhibits the growth of these cancer cells (Freemantle et al Int. J. Tissue React. 17:157, 1995).
Cancer is an aberrant net accumulation of atypical cells that results from an excess of cell proliferation, an insufficiency of cell death, or a combination of the two. Cell proliferation is characterized by replication of total cellular DNA and the division of one cell into two cells (Hochhauser D. Anti-Cancer Chemotherapy Agents 8:903, 1997). Cell death is affected by immune-mediators including, but not limited to, IL-6 and IL-12 that initiate cytolytic processes and that promote apoptosis, and by apoptosis inducers that directly initiate pathways leading to cell death (Muzio et al. Cell 85:817, 1996; Levine, A. Cell 88:323, 1997).
Current cancer treatments act by inhibiting proliferation of cancer cells or by inducing apoptosis in cancer cells. However, many of these treatments have proven to be less than adequate for clinical applications and, at standard dosages, are inefficient or toxic, have significant adverse side-effects, result in development of drug resistance or immunosensitization, are debilitating and compromise the quality of life of the patient. Moreover, the costs of these treatments are substantial, both to the individual patient and to society.
Therefore, there is a continuing need for novel cancer treatments that inhibit proliferation of cancer cells, induce apoptosis in cancer cells, are effective at dose regimens associated with minimal toxicity, and are cost effective.